Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of the common general knowledge in the field.
Kidney disease consists of a diverse range of etiologies, including immunological, mechanical, metabolic and toxic insults amongst others (Hewitson, Fibrogenesis & Tissue Repair 2012, 5(Suppl 1):S14). Regardless of etiology, all patients with chronic kidney disease show a decline in renal function with time, inevitably leading to end-stage renal failure—a condition that requires life-long dialysis or renal transplantation (Hakim & Lazarus, Am J Kidney Dis 1989, 14:396-401). Progressive loss of renal function is associated not only with development of glomerulosclerosis, but also with that of interstitial fibrosis. Interstitial fibrosis is characterized by the destruction of renal tubules and interstitial capillaries, as well as by the accumulation of extracellular matrix proteins (Fukagawa et al., Nephrol Dial Transplant 1999, 14:2793-2795). Kidney fibrosis can lead to hypertension due to increased systemic vascular resistance, with hypertension reported to occur in 85-95% of patients with chronic kidney disease. (Rao et al., Am J Kidney Dis. 2008, 51(suppl 2):S30-S37).
While treatment with angiotensin-converting-enzyme (ACE) inhibitors alone or in combination with angiotensin receptor blockers (ARBs) have been shown to slow the rate of progression of kidney failure, they do not cure kidney disease, i.e., they do not reverse existing fibrosis and restore normal tissue architecture. Additionally, ACE inhibitors and ARBs may cause side effects such as low blood pressure, angioneurotic oedema, hyperkalaemia and persistent dry cough.
Liver disease can be inherited or caused by a variety of factors that damage the liver, such as obesity, diabetes, infections and alcohol abuse. Examples of liver disease include hepatitis, fatty liver disease and cirrhosis.
In fatty liver disease, large vacuoles of triglyceride fat may accumulate in liver cells via steatosis (i.e., abnormal retention of lipids within a cell). This accumulation of fat can cause inflammation, cell death, and scarring.
Left untreated, the damage from fatty liver disease and other liver diseases results in the accumulation of fibrosis, resulting in cirrhosis, liver failure and portal hypertension; often requiring liver transplantation.
There is no standard treatment for liver fibrosis. Although experimental studies have revealed targets to prevent fibrosis progression in rodents, the efficacy of most treatments has not been proven in humans (Bataller & Brenner, J Clin Invest. 2005, 115(2):209-18). At present, treatment usually focuses on treating the cause of liver fibrosis and hoping that the liver regenerates. Treatments aimed at reversing the fibrosis are usually too toxic for long-term use (e.g., corticosteroids, penicillamine) or have no proven efficacy (e.g., colchicine).
Currently there is no pharmacological therapy for hepatic fat accumulation.
There is a need for agents that prevent or treat kidney disease and/or liver disease. In particular, there is a need for agents that prevent, reduce or slow progression of kidney and/or liver fibrosis, reduce established kidney and/or liver fibrosis, prevent, reduce or slow renal tubular cell death, restore normal tissue architecture in the kidney and/or liver, and/or prevent, reduce or slow hepatic fat accumulation.
It is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative.